This invention is in the field of biodegradable, biocompatible polymeric materials, suitable for implantation into a patient""s body.
Many substances used for implants, such as osteochondral implants and orbital implants, e.g., made of hydroxylapatite, are rough and can cause injury to surrounding tissue or interfere with articulation. Smooth implants, however, do not allow for tissue ingrowth and muscle attachment as well as would be desired.
Polymeric films have been used in several types of medical applications in connection with implants. Colomb, G. and Wagner, D. (1991), xe2x80x9cDevelopment of a new in vitro model for studying implantable polyurethane calcification,xe2x80x9d Biomaterials 12:397-405, discloses the use of non-biodegradable polyurethane films 0.2 to 0.7 mm thick to study implant calcification. Bawa, R. and Nandu, M. (1990), xe2x80x9cPhysico-chemical considerations in the development of an ocular polymeric drug delivery system,xe2x80x9d Biomaterials 11:724-728, discloses the use of non-biodegradable silicone-based prepolymer films impregnated with gentamicin sulfate for the fabrication of ocular devices. Marchant, R. E. et al. (1990), xe2x80x9cA hydrophilic plasma polymerized film composite with potential application as an interface for biomaterials,xe2x80x9d J. Biomed. Materials Res. 24:1521-1537, discloses plasma deposition of a first layer polymerized from n-hexane and a second layer polymerized from N-vinyl-2-pyrrolidone to form a 420 nm thick composite film on a non-organic substrate providing a non-cytotoxic covering. Johnson, S. D. et al. (1992), xe2x80x9cBiocompatibility studies in plasma polymerized interface materials encompassing both hydrophobic and hydrophilic surfaces,xe2x80x9d J. Biomed. Materials Res. 26:915-935, discloses that thin plasma-deposited films (about 1 micrometer thick) made from N-vinyl-2-pyrrolidone, xcex3-butyrolactone, hexamethyldisilazane and n-hexane on biomaterials provide good compatibility (reduced toxicity). Plastic and Reconstructive Surgery, December, 1987, 769-774, discloses the use of bioabsorbable Polyglactin 910 (Vicryl(copyright)) film implants for treatment of orbital wall wounds. The film was completely degraded within four months. The films were not seen to affect bone regrowth when compared to controls without the films, but were used to prevent herniation of orbital contents. The film was not used as a covering for another implant material to promote bone or muscle ingrowth. The film did not cause a long-standing inflammatory reaction as did a Dacron-reinforced silicone film to which it was compared. The Polyglactin 910 film used was 0.125 mm (125 micrometers) in thickness. Polyglactin 910 is a 10:90 PLA:PGA polymer film.
Use of a biodegradable polylactic acid (PLA) film 150 micrometers thick was reported in Levy, F. E., et al., xe2x80x9cEffect of a Bioresorbable Film on Regeneration of Cranial Bone,xe2x80x9d Plastic and Reconstructive Surgery, February, 1994, 307-311. After 24 weeks cranial defects covered with the film showed improved healing compared with untreated controls.
Gangadharam, P. R. J. et al. (1994), xe2x80x9cExperimental chemotherapy of tuberculosis using single dose treatment with isoniazid in biodegradable polymers,xe2x80x9d J. Antimicrobial Chemotherapy 33:265-271 discloses the use of a PLA:PGA film containing isoniazid to provide sustained release of the drug for up to four weeks. Details of the preparation of the polymeric film are provided in Gangadharam, P. R. J., et al. (1991), xe2x80x9cSustained release of isoniazid in vivo from a single implant of a biodegradable polymer,xe2x80x9d Tubercle 72:115-122. The film was a 90% lactic/10% glycolic acid polymer having an average polymer molecular weight of 35,000 Daltons. Films containing the drug were prepared by dissolving the polymer in methyl chloride and passing the solution through an 0.8 mm Millipore filter. The drug was added to the solution and the solution was cast onto a clean glass surface as a thin film 0.6 mm in thickness, then air dried, followed by vacuum drying at 45xc2x0 C.
Melalin, R. J. et al. (1990), xe2x80x9cA Biomechanical Study of Tendon Adhesion Reduction Using a Biodegradable Barrier in a Rabbit Model,xe2x80x9d J. Appl. Biomat. 1:13-39, disclosed the use of a knitted cellulose material to reduce adhesion formation.
Monsour, M. J. et al. (1987), xe2x80x9cAn Assessment of a Collagen/Vicryl Composite Membrane to Repair Defects of the Urinary Bladder in Rabbits,xe2x80x9d Urological Res. 15:235-238, and Mohammed, R. et al. (1987), xe2x80x9cThe Use of a Biodegradable Collagen/Vicryl Composite Membrane to Repair Partial Nephrectomy in Rabbitsxe2x80x9d, Urological Res. 15:239-242, discloses a collagen-coated vicryl mesh to facilitate surgical healing. Andriano, K. P. et al. (1995), xe2x80x9cPreliminary Effects of In vitro Lipid Exposure on Absorbable Poly(ortho ester) Films,xe2x80x9d J. Appl. Biomat. 6:129-135, discloses poly(ortho ester) film degradation in vitro in cholesterol emulsions. Hanson, S. J. et al. (1988), xe2x80x9cMechanical Evaluation of Resorbable Copolymers for End Use as Vascular Grafts,xe2x80x9d Trans. Am. Soc. Artif. Intern. Organs 34:789-793, discloses the use of PLA/xcex5-caprolactone materials as vascular graft materials.
None of the foregoing references disclose such films molded or shaped to surround implants made of other materials to improve the biocompatibility of such implants.
Schliephake, H. et al. (1994), xe2x80x9cEnhancement of Bone Ingrowth into a Porous Hydroxylapatite-Matrix Using a Resorbable Polylactic Membrane,xe2x80x9d J. Oral and Maxillofacial Surg. 52:57-63, discloses the use of a polylactic membrane (L/DL-Lactic Acid 70/30) to cover hydroxylapatite blocks placed in mandible and ilium defects. The membrane was nearly completely degraded after five months and the blocks covered with membrane showed more bony penetration of the HA matrix compared to blocks not covered by the membrane. The membrane had been replaced by a thin, fibrous scar. The degradation time was reported as being slow enough to prevent connective tissue cells from penetrating into the block pores so as to allow ingrowth of bone tissue from underlying host bone. The membrane was adapted to the block by a prefabricated, heated metal template which, the reference teaches, may be impossible in a situation where an individual contour is needed due to the rigidity of the polylactic material.
U.S. Pat. No. 5,584,880, issued Dec. 17, 1996 to Martinez for xe2x80x9cOrbital Implantxe2x80x9d discloses an orbital implant comprising hydroxylapatite granules which may be covered by a layer of synthetic material which is preferably a synthetic fabric made of a polymeric material.
None of the foregoing references disclose biodegradable films designed to fit individual contours of implants and to degrade within a short enough period, e.g., less than about four months, to promote rapid muscle and connective tissue attachment to the implant material.
It is therefore an object of this invention to provide biodegradable films which can be used to coat contoured implants, such as rounded hydroxylapatite implants used for orbital reconstruction, or to coat polymeric or other implants to provide improved, smooth articulating surfaces, to improve biocompatibility of the implants and to promote muscle and connective tissue attachment. It is also an object of this invention to provide biodegradable polymeric films designed to have different degradation rates at different locations in the film.
This invention provides a biodegradable, biocompatible polymeric film having a uniform selected thickness between about 60 micrometers and about 5 mm. Films of between about 600 micrometers and 1 mm and between about 1 mm and about 5 mm thick, as well as films between about 60 micrometers and about 1000 micrometers; and between about 60 and about 300 micrometers are useful in the manufacture of therapeutic implants for insertion into a patient""s body. Films between about 60 and about 120 micrometers and between about 75 and about 125 micrometers are also useful in this invention.
The term xe2x80x9cbiodegradablexe2x80x9d means capable of breaking down over time inside a patient""s body. A number of suitable biodegradable polymers for use in making the materials of this invention are known to the art, including polyanhydrides and aliphatic polyesters, preferably polylactic acid (PLA), polyglycolic acid (PGA) and mixtures and copolymers thereof, more preferably 50:50 copolymers of PLA:PGA and most preferably 75:25 copolymers of PLA:PGA. Single enantiomers of PLA may also be used, preferably L-PLA, either alone or in combination with PGA. Polycarbonates, polyfumarates and caprolactones may also be used to make the implants of this invention. The film degradation period should be short enough to allow muscle and connective tissue attachment to the underlying implant, e.g., less than about four months, preferably between about one and about ten weeks and, in some cases, between about one and about three weeks, or no more than about four weeks.
The term xe2x80x9cbiocompatiblexe2x80x9d as used herein with respect to a polymeric film means that the degradation of the film does not elicit an adverse biologic response, that its surfaces are smooth rather than rough or abrasive, and that it is xe2x80x9csubstantially freexe2x80x9d of most residual solvents, such as acetone, meaning that insufficient solvent is present in the film to interfere with cell implantation on or in the implant. Preferably, the film has less than 100 ppm residual solvent. In some cases, where biocompatible solvents such as N-methyl-pyrrolidone (NMP) are used, making the implant substantially solvent-free is not essential.
The polymeric films of this invention are thin compared to their length and breadth, preferably between about 60 micrometers and 5 mm thick. Large, continuous films may be made by the methods of this invention. Typically, sizes of about 11xe2x80x3xc3x9715xe2x80x3 can be made. The polymeric films are uniform in thickness, i.e. not varying in thickness by more than about 30 micrometers. The desired thickness of the film may be selected in advance and controlled in the manufacturing process. These large films can be cut or punched to wafer size, e.g., as described in PCT Publication WO 97/13533 published Apr. 17, 1997, incorporated herein by reference to the extent not inconsistent herewith.
The films are not necessarily flat; they may be shaped or contoured to conform to complex implant contours. Contoured films may be spherical, curved and/or have depressions and bulges and may be designed to fit irregularly-shaped implants including tubular (lumenal) implants.
Bioactive agents such as enhancers of cell attachment, growth factors, enzymes, degradation agents, pH-adjusting agents, therapeutic agents, such as antibiotics, analgesics, chemotherapeutic agents, and the like may be used in conjunction with the polymeric films of this invention. For example, the polymeric films of this invention may be coated by means known to the art with a biologically active agent. Alternatively, such bioactive agents may be incorporated into the thin film by means known to the art. See, e.g., U.S. Pat. No. 6,013,853 or U.S. Pat. No. 5,876,452, incorporated herein by reference to the extent not inconsistent herewith. Such agents, which facilitate attachment of cells to the polymeric material are termed xe2x80x9ccell attachment enhancersxe2x80x9d herein. In addition agents promoting production of various necessary factors within bone, cartilage, muscle or other tissue may be provided, and are included within the term xe2x80x9cgrowth factorsxe2x80x9d herein. Other suitable bioactive agents and methods for their incorporation into biodegradable polymeric materials are known to the art and disclosed, e.g. in U.S. Pat. No. 6,013,853 or U.S. Pat. No. 5,876,452.
A particularly useful growth factor for use in connection with implants designed to encourage cartilage growth, such as osteochondral implants, is P15, a 15 amino acid, MW 1393.6, polypeptide produced by Peptide Innovations, Inc., Southfield, Mich.
The amount of bioactive agent to be incorporated into or coated on the polymeric films of this invention is an amount effective to show a measurable effect in improving the performance of the film-covered implant, as may be known to the art or determined by testing the film-covered implant with and without the bioactive agent and measuring at least one characteristic to be improved.
The films of this invention are used to at least partially wrap or cover therapeutic implants for placement in the body of a patient. The xe2x80x9cpatientxe2x80x9d can be any living organism, including a warm-blooded mammal, and preferably, a human. Covering an implant with a film of this invention provides a smooth surface to avoid abrasion and damage to neighboring tissue, provides a smooth articulating surface, and provides sites for cell ingrowth and attachment. In addition, for highly porous implants, covering with the polymeric films of this invention provides a continuous surface.
In a preferred embodiment, thin films of this invention are used to cover ocular implants, such as those made of hydroxylapatite. The hydroxylapatite is rough, and the smooth surface of the polymer film covering makes the implant more biocompatible in that it is more easily and comfortably implanted and causes less irritation. As the film degrades over a selected period of time, preferably about one to ten weeks, muscle grows into and attaches to the surface of the implant to allow tracking of the artificial eye.
The polymeric films of this invention can also be used to coat metallic implants, such as titanium jaw implants, to facilitate integration of the implant. Portions of the film may be completely degraded over different time periods, as required by the ingrowth of different tissue. Portions of the underlying implant may be left bare, or the film may have holes produced in it so that muscle and/or connective tissue can be attached to the underlying implant by suturing or other means known to the art.
The polymeric films of this invention may be used to provide a thin coating, preferably a PLG coating about 75 to 125 micrometers in thickness on the articulating portion of a single or multiphase osteochondral or chondral implant, for example as described in U.S. Pat. No. 5,607,474, incorporated herein by reference to the extent not inconsistent herewith. The purpose of this coating is to provide a smooth articulating surface on the open celled, cut surface of a wafer such as a polymeric wafer used as an implant. To attach the film, it is merely xe2x80x9cgluedxe2x80x9d on by wetting the implant with acetone or other suitable solvent and then firmly pressing the film onto it. This coating can be altered as described herein to have various degradation rates and thicknesses and may have a bioactive agent incorporated.
The polymeric films of this invention may be made porous or semi-permeable by known foaming techniques or incorporation of porogenic materials such as leachable salts or laser etching. For example, films which allow passage of nutrients but not cells, having pore sizes between about 0.1 micrometers and about 4 micrometers, can be made by laser etching.
A plasticizer may be incorporated in the biodegradable film to make it softer and more pliable for applications where direct contact with a contoured surface is desired. The thin film is plasticized in solutions of N-methyl-pyrrolidone (NMP) or other biocompatible solvent which can be mixed with a co-solvent such as water, ethanol, PEG-400, glycerol, or other co-solvents known to the art. The co-solvent is required to prevent complete dissolution of the polymer. The film is immersed in the solution until as soft as desired, i.e., soft enough to readily conform to the shape of an implant.
The polymeric films of this invention can be formed and used as flat sheets, or can be formed into three-dimensional conformations or xe2x80x9cshellsxe2x80x9d molded to fit the contours of a specific implant. For example, to cover ocular implants which are spherical in form, polymeric films of this invention can be formed in two hemispheres. The implant can be encapsulated in two halves and the coating fused to form a continuous coating. The films may also be molded or pressed, using heat for softening, into more complicated contours. The film is also provided as a plasticized sheet for use at the time of implantation. A biocompatible solvent as described above makes the film capable of being easily stretched to form around a contoured surface of the implant. The film adheres to itself and can be stretched up to about 200% without tearing. Prior to implantation of the sterile implant, it can be xe2x80x9cwrappedxe2x80x9d with the plasticized film.
The films of this invention can be designed so that they degrade at different rates in different zones (areas) of the film and/or release or incorporate different bioactive agents in different zones. Porosities, thickness and other properties may also be varied in different zones. This may be desirable so that surface areas of an implant at attachment zones for muscle or other tissue can be made more rapidly degradable and/or porous, while surface areas not required for immediate tissue ingrowth can be made more slowly degradable and/or thicker to provide controlled release of an incorporated bioactive agent. Additionally, implant surfaces near the exterior of the body can be made less rapidly degradable and/or porous to provide better protection against bacterial attack, while inner surfaces can be made more rapidly degradable and/or porous to encourage tissue ingrowth.